Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model.

Murine studies have shown that immunological targeting of fibroblast activation protein (FAP) can elicit protective immunity in the absence of significant pathology. Fibroblast activation protein is a product overexpressed by tumor-associated fibroblasts (TAF) and is the predominant component of the stoma in most types of cancer. Tumor-associated fibroblasts differ from normal adult tissue fibroblasts, and instead resemble transient fetal and wound healing-associated fibroblasts. Tumor-associated fibroblasts are critical regulators of tumorigenesis, but differ from tumor cells by being more genetically stable. Therefore, in comparison to tumor cells, TAF may represent more viable therapeutic targets for cancer immunotherapy. To specifically target TAF, we constructed a DNA vaccine directed against FAP. This vaccine significantly suppressed primary tumor and pulmonary metastases primarily through CD8(+) T-cell-mediated killing in tumor-bearing mice. Most importantly, tumor-bearing mice vaccinated against FAP exhibited a 1.5-fold increase in lifespan and no significant pathology. These results suggest that FAP, a product preferentially expressed by TAF, could function as an effective tumor rejection antigen.

Wen Y ，Wang CT ，Ma TT ，Li ZY ，Zhou LN ，Mu B ，Leng F ，Shi HS ，Li YO ，Wei YQ ... -  《-》

Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model.

Xia Q ，Zhang FF ，Geng F ，Liu CL ，Xu P ，Lu ZZ ，Yu B ，Wu H ，Wu JX ，Zhang HH ，Kong W ，Yu XH ... -  《-》

Improvement of anti-tumor immunity of fibroblast activation protein α based vaccines by combination with cyclophosphamide in a murine model of breast cancer.

Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts (CAFs), which are the main type of cells in the tumor microenvironment. CAFs exert immunosuppressive activity, which can weaken the effects of cancer immunotherapy and mainly account for poor outcomes with therapeutic vaccines. To better target and destroy CAFs, a FAPα vaccine using a modified vaccinia ankara (MVA) vector was constructed and used with a DNA vaccine reported in our previous work for heterologous prime-boost immunizations in mice. This strategy to generate anti-tumor immunity partly reduced 4T1 tumor growth through producing FAPα-specific cytotoxic T lymphocyte responses in a preventive model, but the effect required improvement. Combining the FAPα-based cancer vaccines (CpVR-FAP/MVA-FAP) with cyclophosphamide (CY), which can be used not only as a chemotherapeutic but also an immunomodulatory agent to promote a shift from immunosuppression to immunopotentiation, resulted in markedly enhanced tumor growth inhibition compared with the CpVR-FAP/MVA-FAP group. This strategy achieved synergistic effects in a therapeutic model by improving the tumor inhibition rate by 2.5-fold (90.2%), significantly enhancing cellular immunity and prolonging the survival of 4T1 tumor-bearing mice by 35% compared with the PBS group. Furthermore, CAFs, stromal factors and immunosuppressive factors such as IL-10 and Tregs were also markedly decreased by the CY combination. These results indicated that FAPα-targeted MVA boosting in combination with CY is an effective approach to improving specific anti-tumor immune responses through overcoming immunosuppression. This study may offer important advances in research on clinical cancer immunotherapies by modulating immunosuppressive factors.

Xia Q ，Zhang FF ，Geng F ，Liu CL ，Wang YQ ，Xu P ，Lu ZZ ，Xie Y ，Wu H ，Chen Y ，Zhang Y ，Kong W ，Yu XH ，Zhang HH ... -  《-》

A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

Chen M ，Xiang R ，Wen Y ，Xu G ，Wang C ，Luo S ，Yin T ，Wei X ，Shao B ，Liu N ，Guo F ，Li M ，Zhang S ，Li M ，Ren K ，Wang Y ，Wei Y ... -  《Scientific Reports》

Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake.

Loeffler M ，Krüger JA ，Niethammer AG ，Reisfeld RA ... -  《-》